Abstract
Majoranolide, a butanolide isolated from the nonpolar fraction of an ethanol extract of Mezilaurus crassiramea (Lauraceae) fruits, is being reported for the first time in this genus and the third time in plants. Structurally identified from 1D and 2D NMR and HRESIMS data, majoranolide proved cytotoxic against cancer cells—MCF-7 and MDA-MB-231 (breast), HT-29 (colon), PC-3 (prostate), 786-0 (renal), and HL-60 (leukemia)—inhibiting growth in HL-60 cells (GI50 = 0.21 μM) and exhibiting higher selectivity for this line than for nonneoplastic NIH/3T3 murine fibroblasts. Effects on the cell cycle, caspase-3 activation, and plasma membrane integrity were evaluated by flow cytometry. Expression of genes related to apoptotic pathways (BAX, BCL2, BIRC5, and CASP8) was investigated using RT-qPCR. At 50 μM, majoranolide induced cell cycle arrest at G1 in 24 h increased the sub-G1 population in 48 h and increased caspase-3 activation in a time-dependent manner. The compound upregulated BAX and CASP8 transcription (proapoptotic genes) and downregulated BIRC5 (antiapoptotic). Loss of plasma membrane integrity in 30% of cells occurred at 48 h, but not at 24 h, characterizing gradual, programmed death. The results suggest that majoranolide cytotoxicity involves apoptosis induction in HL-60 cells, although other mechanisms may contribute to this cell death.
Highlights
Mezilaurus crassiramea (Meisn.) Taub. ex Mez. (Lauraceae), a tree commonly found in Mato Grosso do Sul state, Midwest Brazil, occurs frequently in Cerrado landscapes on the Brazilian Plateau [1].Previous investigation of the activity of the species’ leaf extracts against brine shrimp (Artemia salina) led to the isolation of three butanolides, namely, rubrenolide and its corresponding 2- and 2,3-acetyl derivatives, that proved cytotoxic to human cancer cells [2].Several compounds obtained from Lauraceae bearing a γbutyrolactone backbone have received considerable attention for their potential cytotoxicity [3,4,5,6]
This article reports the isolation of majoranolide, a butanolide, and the investigation of its cytotoxicity against a panel of human neoplastic cell lines
Our results demonstrate that the cytotoxic effect of majoranolide induces apoptosis in HL-60 cells
Summary
Mezilaurus crassiramea (Meisn.) Taub. ex Mez. (Lauraceae), a tree commonly found in Mato Grosso do Sul state, Midwest Brazil (vernacular names: “canela-branca”, “canela-degoias”, “cumbuquinha”, “itauba-abacate”), occurs frequently in Cerrado landscapes on the Brazilian Plateau [1].Previous investigation of the activity of the species’ leaf extracts against brine shrimp (Artemia salina) led to the isolation of three butanolides, namely, rubrenolide and its corresponding 2- and 2,3-acetyl derivatives, that proved cytotoxic to human cancer cells [2].Several compounds obtained from Lauraceae bearing a γbutyrolactone backbone have received considerable attention for their potential cytotoxicity [3,4,5,6]. Previous investigation of the activity of the species’ leaf extracts against brine shrimp (Artemia salina) led to the isolation of three butanolides, namely, rubrenolide and its corresponding 2- and 2,3-acetyl derivatives, that proved cytotoxic to human cancer cells [2]. Relapse and drug resistance are other problems affecting success in cancer therapy. These obstacles have stimulated the search for potent, selective molecules that can serve as anticancer drugs [7, 8]. As part of our group’s efforts to identify novel constituents with potential anticancer activity in M. crassiramea, the present investigation was conducted using fruits of this species. An evaluation of the effects of the compound on the cell cycle of HL-60 cells and the apoptosis process demonstrated in vitro the anticancer potential of majoranolide
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